ABSTRACT Aging drives the development of cardiac hypertrophy, an independent risk factor for heart failure, coronary heart disease, and other cardiovascular events that affect millions of people worldwide. The pathogenesis of age-related cardiac hypertrophy is governed by blood-borne factors, and prior seminal studies have identified growth differentiation factor 11 (GDF11) as a prominent systemic regulator of the condition. In those studies, a natural decline in blood GDF11 levels coincided with the onset of cardiac hypertrophy in old mice, and treatment with recombinant GDF11 reversed the hypertrophic effects. Recent efforts have challenged those initial findings, suggesting that: 1) GDF11 levels may also increase over time, an alteration that appears to promote cardiac hypertrophy, and 2) some of the effects previously attributed to GDF11 may in fact be caused by its homolog, myostatin (GDF8). As a result, there is a critical need to define the true relationship between GDF11 levels and age-related cardiac hypertrophy, and to identify the major determinants of that relationship. The disparate findings to this point demand novel approaches to address the knowledge gaps, and to this end, the proposed project will employ a novel systems approach to determine the impact of genetic variation on circulating GDF11 levels and their effects on age-related cardiac hypertrophy. Our overarching hypothesis predicts that the GDF11 paradigm, wherein changes in GDF11 levels drive age-related cardiac hypertrophy, is strongly influenced by genetic factors. To test that hypothesis, we will use the revolutionary Diversity Outbred (DO) stock, and its eight founder strains, to address the following specific aims: 1) To validate the relationship between GDF11 and cardiac hypertrophy, and to test whether the relationship is dependent on genetic background; and 2) To define the genetic architecture of GDF11 levels using the DO, and to contrast the results against the genes that underlie cardiac hypertrophy. For each aim, we will use mass spectrometry to distinguish and quantify GDF11 and myostatin, enabling us to unambiguously differentiate between these proteins and to characterize the unique effects of GDF11 on age-related cardiac hypertrophy. These studies will reveal the underlying genetic contributors to circulating GDF11 levels, and the identification of novel genes will add critical and fresh insights into the fundamental biological pathways that couple advanced age and cardiac hypertrophy. Knowledge gained from these efforts will directly contribute to the ultimate goal of developing effective treatment strategies against age-related cardiovascular disease.